Project Summary/Abstract: Cardiac transplantation is the ultimate treatment option for patients with end stage heart failure. Cardiac allograft vasculopathy remains a leading cause of morbidity and mortality after transplantation. Dyslipidemia is a major contributor to cardiac allograft vasculopathy and is suboptimally controlled with current medications. The PCSK9 inhibitors are novel lipid lowering agents which have been shown to significantly lower cholesterol levels and lead to coronary plaque regression in non-transplant individuals. This class of medication has not been tested in cardiac transplant recipients. The objective of this project is to investigate the safety and efficacy of the PCSK9 inhibitor, alirocumab in preventing the development of cardiac allograft vasculopathy. During the first month after cardiac transplantation subjects will undergo coronary angiography with intravascular ultrasound measurements of plaque, vessel and lumen volumes in the left anterior descending coronary artery. Using a coronary pressure wire, epicardial artery and microvascular physiology will be assessed. Finally, endothelial function will be assayed. Subjects will then be randomized in a double blind fashion to either alirocumab or placebo. Baseline and serial lipid values and inflammatory markers will be measured. After 1 year, the above assessment will be repeated. The primary endpoint is the change in plaque volume based on intravascular ultrasound assessment. Secondary endpoints will be the effect of alirocumab on coronary physiology, endothelial function and inflammatory markers. An important secondary aim of this project is to investigate the role of coronary physiology and endothelial function assessment for predicting cardiac allograft vasculopathy, independent of intravascular ultrasound findings. We believe this project will contribute significantly to the evidence base for an important health matter, namely the optimal medical treatment of cardiac transplant recipients.